The purpose of this proposal is to cultivate the scientific development and advance the research skills of Dr. William Lawson, so that he may become an independent investigator. Dr. Lawson is currently developing his academic career in the Center for Lung Research at Vanderbilt University Medical Center (VUMC). VUMC provides an environment conducive to developing physician-scientists through its many laboratory resources, educational opportunities, and expert faculty. Under guidance by Dr. Timothy Blackwell, Dr. Lawson will design and perform experiments that will enhance his knowledge and research skills in the pathobiology of pulmonary fibrosis. Through laboratory experience and formal coursework, he will gain expertise in experimental design and execution, transgenic murine model development, cell and molecular biology techniques, statistical analysis, and reporting of results. These skills will provide the foundation for Dr. Lawson to pursue an independent academic career in pulmonary fibrosis research. In Idiopathic Pulmonary Fibrosis (IFF), progressive parenchymal fibrosis disrupts the structure and gas exchanging functions of the lungs, with fibroblasts largely responsible for the augmented collagen and matrix deposition. The origin of lung fibroblasts during pulmonary fibrosis has not been well defined, but potential sources include proliferation of resident interstitial lung fibroblasts, differentiation of progenitor cells from the bone marrow, and transition of epithelial cells to a fibroblast phenotype, a process termed epithelial-mesenchymal transition (EMT). In preliminary data, we present evidence that EMT is a major contributor to the lung fibroblast population in experimentally induced pulmonary fibrosis. For this proposal, we have formed the following hypothesis: Epithelial cells and mesenchymal cells in the lung are capable of phenotypic transitions during pulmonary fibrosis. During lung fibrosis, fibroblasts can arise from airway epithelial cells through epithelial-mesenchymal transition, and during resolution fibroblasts can resume an epithelial cell phenotype. Modulating factors that regulate epithelial-mesenchymal transition will limit progression and promote resolution of lung fibrosis. To test this hypothesis, we have developed the following specific aims: 1) to define the contribution of epithelial-mesenchymal transition to the lung fibroblast population in pulmonary fibrosis; 2) to characterize key pathways involved in epithelial-mesenchymal transition in type II alveolar epithelial cells; and 3) to determine the effects of attenuating or reversing epithelial-mesenchymal transition on the progression and resolution of lung fibrosis. IPF remains a disease with a dire prognosis greatly in need of effective treatment strategies. Defining the role of EMT in the lung and delineating critical pathways involved in this cellular plasticity could lead to novel therapeutic strategies to limit disease progression in IPF and other forms of lung fibrosis.